Cancer immunotherapy restores or enhances the effector function of T cells in the tumor microenvironment, but the efficacy of immunotherapy has been hindered by therapeutic resistance. Here, we identify the proto-oncogene serine/threonine protein kinase PIM2 as a novel negative feedback regulator of IFNγ-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1β derived from IFNγ-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-κB signaling pathways. PIM2+ cancer cells generated by proinflammatory macrophages acquired the capability to survive, metastasize, and resist T-cell cytotoxicity and immunotherapy. A therapeutic strategy combining immune checkpoint blockade (ICB) with IL1β blockade or PIM2 kinase inhibition in vivo effectively and successfully elicited tumor regression. These results provide insight into the regulatory and functional features of PIM2+ tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy. Significance: Cross-talk between T cells and macrophages regulates cancer cell PIM2 expression to promote cancer aggressiveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma.

中文翻译：

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促炎巨噬细胞诱导的 PIM2 表达抑制肝细胞癌的免疫治疗效果

癌症免疫疗法可以恢复或增强肿瘤微环境中T细胞的效应功能，但免疫疗法的疗效却因治疗耐药性而受到阻碍。在这里，我们将原癌基因丝氨酸/苏氨酸蛋白激酶PIM2确定为IFNγ引起的肿瘤炎症的新型负反馈调节因子，从而赋予癌细胞侵袭性特征。从机制上讲，源自 IFNγ 极化肿瘤巨噬细胞的 IL1β 通过 p38 MAPK/Erk 和 NF-κB 信号通路触发癌细胞中 PIM2 的表达。由促炎巨噬细胞产生的 PIM2+ 癌细胞获得了生存、转移和抵抗 T 细胞的细胞毒性和免疫治疗的能力。将免疫检查点阻断（ICB）与IL1β阻断或体内PIM2激酶抑制相结合的治疗策略有效并成功地引起肿瘤消退。这些结果提供了对 PIM2+ 肿瘤的调控和功能特征的深入了解，并表明影响炎症细胞或 PIM2 激酶功能活动的策略可能会提高免疫治疗的疗效。意义：T 细胞和巨噬细胞之间的串扰调节癌细胞 PIM2 表达以促进癌症侵袭性，揭示了改善肝细胞癌对 ICB 反应的转化方法。这些结果提供了对 PIM2+ 肿瘤的调控和功能特征的深入了解，并表明影响炎症细胞或 PIM2 激酶功能活动的策略可能会提高免疫治疗的疗效。意义：T 细胞和巨噬细胞之间的串扰调节癌细胞 PIM2 表达以促进癌症侵袭性，揭示了改善肝细胞癌对 ICB 反应的转化方法。这些结果提供了对 PIM2+ 肿瘤的调控和功能特征的深入了解，并表明影响炎症细胞或 PIM2 激酶功能活动的策略可能会提高免疫治疗的疗效。意义：T 细胞和巨噬细胞之间的串扰调节癌细胞 PIM2 表达以促进癌症侵袭性，揭示了改善肝细胞癌对 ICB 反应的转化方法。